Download emergency medical treatment protocol

EMERGENCY MEDICAL TREATMENT PROTOCOL
FOR
ACCIDENTAL EXPOSURE TO MPTP
1. Remove any contaminated clothing.
2. Rinse any contaminated skin surfaces copiously with water.
3. Have the exposed employee take 6 (six) 5 mg. tablets of Selegiline (Eldepryl) by
mouth as soon as possible.*
4. Exposed employee should report or be transported to the Boston Medical Center
Emergency Department at East Newton Campus (617–638–6420).
It is important that the exposed employee not drive him or herself at this time due to
the potential for hypotension (low blood pressure) from Selegiline. Should the
exposed employee lose consciousness prior to transport, place them on the floor on
their back and elevate their legs. Do not attempt to transport an unconscious person
but call Security at (638–4444) to arrange transport to the emergency room by
ambulance.
* It is the responsibility of the Principal Investigator to make sure that a supply of
Selegiline be available to all researchers with potential exposure to MPTP in his/her
laboratory. It is the responsibility of the Principal Investigator to reorder Selegiline prior
to the expiration date from a physician at the Boston Medical Center Occupational &
Environmental Medicine Department.
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POTENTIAL FOOD AND DRUG INTERACTIONS
WITH
SELEGILINE (ELDEPRYL)1
Selegiline (Eldepryl) potentially interacts with many foods, prescription drugs, and nonprescription drugs with serious and sometimes fatal consequences. Selegiline is a
member of a class of drugs known as monoamine oxidase inhibitors (MAOIs).
Hypertensive crises may occur when patients taking MAOIs consume foods that contain
large amounts of tyramine and tryptophan. Agents that selectively inhibit monoamine
oxidase type B (such as Selegiline) are theoretically less likely to cause hypertensive
crises than agents that nonselectively inhibit MAO. However, caution is recommended
for all patients, especially when higher than recommended doses are prescribed, as for
treatment for MPTP exposure. When Selegiline is used in high doses, it is recommended
that the patient avoid the following foods:
(Contraindicated foods while working with MPTP starting 24
hours prior to working with MPTP)
Cheese (particularly strong, aged, or processed cheeses)
Sour cream
Wine (particularly red wine)
Champagne
Beer
Herring
Anchovies
Caviar
Shrimp paste
Liver (particularly chicken liver)
Sausage
Figs
Raisins
Bananas
Avocados
Chocolate
Soy sauce
Bean curd
Yogurt
Papaya products
Meat tenderizers (e.g., Adolphs)
Fava beans
Protein extracts
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Dietary supplements.
Caffeine may also precipitate hypertensive crises and should be avoided.
CONTRAINDICATED MEDICATIONS WITH SELEGILINE
(ELDEPRYL)
Numerous prescription and over the counter medications may interact with
Selegiline. Be sure to discuss any medications that you are currently taking with
the physician who screens you to work with MPTP and DO NOT BEGIN ANY
MEDICATIONS without first consulting the physician.
Tricyclic antidepressants: Dibenzazepine Derivative Drugs by generic name
follows:
Pamelor (nortriptyline hydrochloride)
Elavil (amitriptyline hydrochloride)
(perphenazine and amitriptyline hydrochloride)
(clomipramine hydrochloride)
Norpramin(desipramine hydrochloride)
(imipramine hydrochloride)
Sinequan(doxepin)
Tegretol (carbamazepine)
Flexeril (cyclobenzaprine HCl)
Asendin (amoxapine)
maprotiline HCl
Surmontil (trimipremine maleate)
Vivacil (protriptyline HCl)
Remeron (mirtazapine)
Ephedrine containing medications
MAO Inhibitors:
Nardil (phenelzine sulfate)
Parnate (pargyline hydrochloride)
Furoxone(furazolidone)
(isocarboxazid)
(procarbazine)
(tranylcypromine)
BuSpar (buspirone HCl)
Opioids: including Demerol (meperidine)
Serotonergic Drugs:
Prozac (fluoxetine hydrochloride)
Paxil (paroxetine)
dexfenfluraine
Luvox (fluvoxmine)
Zoloft (sertraline)
Effexor (venlafaxine)
Antihypertensive drugs including thiazide diuretics (methylclothiazide)
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and beta blockers
Over–the Counter Medication to Avoid
Cold and cough preparations (including those containing Dextromethorphan)
Nasal decongestants (tablets, drops, or sprays)
Hay–fever medications
Sinus medications
Asthma inhalant medications
Anti–appetite medications
Weight-reducing preparations
“Pep” pills
L–tryptophan containing preparations
REMEMBER! As soon as you begin working with MPTP you will be at risk for taking
Selegiline at any time. The above food restrictions should begin at least 24 hours prior to
beginning work with MPTP and need to be continued until your risk of exposure is over.
If you have been taking certain medications, these medications must be restricted prior to
working with MPTP for up to several weeks prior to working with MPTP depending on
the specific medication. You must continue to avoid medications that are contraindicated
with Selegiline until your risk of exposure is over.
It is important for the person who will be at risk of exposure to MPTP to know that there
is no human clinical experience regarding attempts to treat acute exposure to MPTP with
MAOIs and that the theoretical benefit of such attempts is based on data from animal
experimentation.
If you have questions about any medication you are taking, prescription or over the
counter with regard to its potential interaction with Selegiline, you must contact Cheryl
Barbanel, MD, at BMC Occupational & Environmental Medicine (617–638–8410) or a
neurologist in the movement disorder clinic (617–638–8456) prior to working with
MPTP. See Appendix A.
Risks and Precautions to take when working with MPTP have been reviewed
with me and I have been given a copy of the MPTP medical surveillance protocol.
__________________________________
Signature of Researcher
__________________________________
Clinician
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____________________
Date
PROTOCOL FOR MEDICAL EVALUATION
OF A WORKER
EXPOSED TO MPTP
MPTP (methyl–phenyl –tetrahydro-pyridine) and its analogs are neurotoxins used in
animal models to simulate Parkinson’s syndrome. Low dose exposures may cause
irreversible neurologic damage to dopamine neurons. A percutaneous exposure to
MPTP is a genuine emergency. Immediate treatment with a MAOI may prevent the
conversion of MPTP to its toxic metabolites. This recommendation is based on animal
data only. There has been no human clinical experience documenting the benefit of this
use of MAOIs.
1. Contact the Boston Medical Center Emergency Department on the East Newton
Campus at (638–6420) to report the exposure prior to the arrival or transporting of
the exposed employee (patient), if possible.
2. If 6 (six) 5mg. tablets of Selegiline (Eldepryl) have not been administered by
mouth at the time the call is received at the BMC OEM, instruct the employee to
do this at once. (The medication is to be available on site.)
3. If the patient is ambulatory have the patient report to the BMC Emergency
Department (ED). The patient is NOT to drive him or herself at this time! If
the patient is not ambulatory call Security at 638–4444 to arrange transport by
ambulance for patient to the BMC ED. Take this Protocol with the patient and
provide it to the attending physician. The remaining Selegiline (Eldepryl)
(Deprenyl) should be carried with the patient to the ED.
4. The attending physician obtains a brief medical history, including an estimate of
the amount of MPTP involved.
5. The attending physician performs a focused physical exam of the injury site and
then performs a thorough neurological exam noting any evidence of tremors,
motor weakness, or rigidity. Temperature, respiratory rate, pulse, and blood
pressure are obtained including postural readings of pulse and blood pressure in
the supine, sitting, and standing positions. Vital signs should be monitored for 2
hours.
6. The attending physician contacts the Movement Disorder Clinic Physician
through the on call neurologist at 617–638–8456. (Appendix A3: Movement
Disorder Physicians)
7. The patient is instructed to take 3 (three) 5 mg. tablets of Selegiline twice a day
for the next 3 (three) days.
8. The potential adverse reactions of Selegiline are reviewed with the patient, as are
the dietary and medication precautions to be taken. It is important to remind the
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patient that dietary precautions and drug restrictions need to be continued for 2 to
4 weeks after Selegiline is given in order to minimize the possibility of
interaction.
9. The patient is reevaluated daily for the next 3 (three) days at the Movement
Disorder Clinic.
1
Appendix B: PDR on Eldepryl
Appendix C: PDR on Nardil
3
Appendix A: Important Contact Information
2
References:
1. Przedborski et al (2001) The parkinsonian toxin 1–methyl–4–phenyl–1,2,3,6tetrahydropyridind (MPTP): a technical review of its utility and safety. J
neurochem. Mar: 76(5):1265–74.
2. Personal Communication with Serge Przedborski at Columbia University.
3. Personal Communication with Dr. Michael Schwarzchild at MGH
4. PDR: Eldepryl Capsules, and Nardil
5. NIH Procedures for working with MPTP and animals
6. Monoamine Oxidase Inhibitors in Neurological Diseases, eds: Abraham
Lieberman, C Warren Olanow, Moussa B H Youdim, Keith Tipton
Marcel Dekker, Inc., New York, Basel, Hong Kong, 1994
The protocol is based on the NIH protocol. The committee adapted this protocol for
BUMC. An ad hoc MPTP Committee was met on 10/18/02 and 12/17/02. The MPTP
Committee reviewed current recommendations in the literature on medical surveillance
for MPTP, current practices of investigators performing research with MPTP, and known
information on the metabolism of Selegiline. The committee participants included,
Neurologist, Marie St. Hilaire, MD, Dr. Mark Moss, PhD, Chairman of Neurobiology,
Jiang-Fan Chen, MD, PhD, PI, working at BUSM with MPTP and Cheryl Barbanel, MD,
MBA, MPH (Chair), Chief of Occupational Medicine at BMC.
Additional consultants included Robert Feldman, MD, Serge Przedborski, MD, PhD,
Columbia University, Michael Schwarzschild, MD, PhD, MGH, and occupational
medicine physician RonVoight, MD, at Care Group.
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Appendix A
Important Contact Information
Movement Disorder Clinic 617–638–8456
BMC Department of Neurology
Marie St. Hilaire, MD
Samuel Ellias, MD
Peter Novak, MD
Security (617) 638–4444
Control (617) 638–4144
Environmental Health & Safety (617) 638–8830
BMC Occupational & Environmental Medicine 617–638–8400
Cheryl Barbanel, MD (617) 638–8410 or (617) 353–6630
This protocol was prepared by Cheryl Barbanel, MD, MBA, MPH. Please contact Dr.
Barbanel, if information needs to be updated on this protocol or appendix at (617) 638–
8410).
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Appendix B
Physicians’ Desk Reference Information on Selegiline (Eldepryl)
PHYSICIANS' DESK REFERENCE
-----------------------------------------------------------------------PDR® entry for
Eldepryl Capsules (Somerset)
DESCRIPTION
CHEMICAL STRUCTURE
CLINICAL PHARMACOLOGY
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
DRUG INTERACTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
PRODUCT PHOTO(S)
DESCRIPTION
ELDEPRYL (Selegiline hydrochloride) is a levorotatory acetylenic derivative of phenethylamine. It is
commonly referred to in the clinical and pharmacological literature as l-deprenyl.
The chemical name is: (R)-(-)- N,2 -dimethyl- N-2 -propynylphenethylamine hydrochloride. It is a white to
near white crystalline powder, freely soluble in water, chloroform, and methanol, and has a molecular
weight of 223.75. The structural formula is as follows:
Each aqua blue capsule is band imprinted with the Somerset logo on the cap and "Eldepryl 5 mg" on the
body. Each capsule contains 5 mg Selegiline hydrochloride. Inactive ingredients are citric acid, lactose,
magnesium stearate, and microcrystalline cellulose.
CLINICAL PHARMACOLOGY
The mechanisms accounting for Selegiline's beneficial adjunctive action in the treatment of Parkinson's
disease are not fully understood. Inhibition of monoamine oxidase (MAO), type B, activity is generally
considered to be of primary importance; in addition, there is evidence that Selegiline may act through other
mechanisms to increase dopaminergic activity.
Selegiline is best known as an irreversible inhibitor of (MAO), an intracellular enzyme associated with the
outer membrane of mitochondria. Selegiline inhibits MAO by acting as a 'suicide' substrate for the
enzyme; that is, it is converted by MAO to an active moiety, which combines irreversibly with the active
site and/or the enzyme's essential FAD cofactor. Because Selegiline has greater affinity for type B rather
than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the
recommended dose.
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MAOs are widely distributed throughout the body; their concentration is especially high in liver, kidney,
stomach, intestinal wall, and brain. MAOs are currently subclassified into two types, A and B, which differ
in their substrate specificity and tissue distribution. In humans, intestinal MAO is predominantly type A,
while most of that in brain is type B.
In CNS neurons, MAO plays an important role in the catabolism of catecholamines (dopamine,
norepinephrine and epinephrine) and serotonin. MAOs are also important in the catabolism of various
exogenous amines found in a variety of foods and drugs. MAO in the GI tract and liver (primarily type A),
for example, is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the
capacity, if absorbed intact, to cause a `hypertensive crisis,' the so–called `cheese reaction.' (If large
amounts of certain exogenous amines gain access to the systemic circulation – e.g., from fermented
cheese, red wine, herring, over–the–counter cough/cold medications, etc. – they are taken up by adrenergic
neurons and displace norepinephrine from storage sites within membrane bound vesicles. Subsequent
release of the displaced norepinephrine causes the rise in systemic blood pressure, etc.)
In theory, since MAO A of the gut is not inhibited, patients treated with Selegiline at a dose of 10 mg a day
should be able to take medications containing pharmacologically active amines and consume tyramine–
containing foods without risk of uncontrolled hypertension. Although rare, a few reports of hypertensive
reactions have occurred in patients receiving Eldepryl at the recommended dose, with tyramine–containing
foods. In addition, one case of hypertensive crisis has been reported in a patient taking the recommended
dose of Selegiline and a sympathomimetic medication, ephedrine. The pathophysiology of the `cheese
reaction' is complicated and, in addition to its ability to inhibit MAO B selectively, Selegiline's relative
freedom from this reaction has been attributed to an ability to prevent tyramine and other indirect acting
sympathomimetics from displacing norepinephrine from adrenergic neurons. However, until the
pathophysiology of the cheese reaction is more completely understood, it seems prudent to assume that
Selegiline can ordinarily only be used safely without dietary restrictions at doses where it presumably
selectively inhibits MAO B (e.g., 10 mg/day).
In short, attention to the dose dependent nature of Selegiline's selectivity is critical if it is to be used
without elaborate restrictions being placed on diet and concomitant drug use although, as noted
above, a few cases of hypertensive reactions have been reported at the recommended dose. (See
WARNINGS and PRECAUTIONS .)
It is important to be aware that Selegiline may have pharmacological effects unrelated to MAO B
inhibition. As noted above, there is some evidence that it may increase dopaminergic activity by other
mechanisms, including interfering with dopamine re–uptake at the synapse. Effects resulting from
Selegiline administration may also be mediated through its metabolites. Two of its three principal
metabolites, amphetamine and methamphetamine, have pharmacological actions of their own; they
interfere with neuronal uptake and enhance release of several neurotransmitters (e.g., norepinephrine,
dopamine, serotonin). However, the extent to which these metabolites contribute to the effects of
Selegiline are unknown.
Rationale for the Use of a Selective Monoamine Oxidase Type B Inhibitor in Parkinson's Disease:
Many of the prominent symptoms of Parkinson's disease are due to a deficiency of striatal dopamine that is
the consequence of a progressive degeneration and loss of a population of dopami–nergic neurons which
originate in the substantia nigra of the midbrain and project to the basal ganglia or striatum. Early in the
course of Parkinson's Disease, the deficit in the capacity of these neurons to synthesize dopamine can be
overcome by administration of exogenous levodopa, usually given in combination with a peripheral
decarboxylase inhibitor (carbidopa).
With the passage of time, due to the progression of the disease and/or the effect of sustained treatment, the
efficacy and quality of the therapeutic response to levodopa diminishes. Thus, after several years of
levodopa treatment, the response, for a given dose of levodopa, is shorter, has less predictable onset and
offset (i.e., there is `wearing off'), and is often accompanied by side effects (e.g., dyskinesia, akinesias, on–
off phenomena, freezing, etc.).
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This deteriorating response is currently interpreted as a manifestation of the inability of the ever–decreasing
population of intact nigrostriatal neurons to synthesize and release adequate amounts of dopamine.
MAO B inhibition may be useful in this setting because, by blocking the catabolism of dopamine, it would
increase the net amount of dopamine available (i.e., it would increase the pool of dopamine). Whether or
not this mechanism or an alternative one actually accounts for the observed beneficial effects of adjunctive
Selegiline is unknown.
Selegiline's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa.
Whether or not it might be effective as a sole treatment is unknown, but past attempts to treat Parkinson's
disease with non–selective MAOI monotherapy are reported to have been unsuccessful. It is important to
note that attempts to treat Parkinsonian patients with combinations of levodopa and currently marketed
non-selective MAO inhibitors were abandoned because of multiple side effects including hypertension,
increase in involuntary movement, and toxic delirium.
Pharmacokinetic Information (Absorption, Distribution, Metabolism and Elimination--ADME):
The absolute bioavailability of Selegiline following oral dosing is not known; however, Selegiline
undergoes extensive metabolism (presumably attributable to presystemic clearance in gut and liver). The
major plasma metabolites are N–desmethylSelegiline, L–amphetamine and L–methamphetamine. Only N–
desmethylSelegiline has MAO–B inhibiting activity. The peak plasma levels of these metabolites
following a single oral dose of 10 mg are from 4 to almost 20 times greater than that of the maximum
plasma concentration of Selegiline [1 ng/mL]. The maximum concentrations of amphetamine and
methamphetamine, however, are far below those ordinarily expected to produce clinically important
effects.
Single oral dose studies do not predict multiple dose kinetics, however. At steady state the peak plasma
level of Selegiline is 4 fold that obtained following a single dose. Metabolite concentrations increase to a
lesser extent, averaging 2 fold that seen after a single dose.
The bioavailability of Selegiline is increased 3 to 4 fold when it is taken with food.
The extent of systemic exposure to Selegiline at a given dose varies considerably among individuals.
Estimates of systemic clearance of Selegiline are not available. Following a single oral dose, the mean
elimination half–life of Selegiline is two hours. Under steady state conditions the elimination half-life
increases to ten hours.
Because Selegiline's inhibition of MAO–B is irreversible, it is impossible to predict the extent of MAO-B
inhibition from steady state plasma levels. For the same reason, it is not possible to predict the rate of
recovery of MAO–B activity as a function of plasma levels. The recovery of MAO–B activity is a function
of de novo protein synthesis; however, information about the rate of de novo protein synthesis is not yet
available. Although platelet MAO–B activity returns to the normal range within 5 to 7 days of Selegiline
discontinuation, the linkage between platelet and brain MAO–B inhibition is not fully understood nor is the
relationship of MAO–B inhibition to the clinical effect established (see Clinical Pharmacology).
Special Populations:
Renal Impairment:
No pharmacokinetic information is available on Selegiline or its metabolites in renally impaired subjects.
Hepatic Impairment:
No pharmacokinetic information is available on Selegiline or its metabolites in hepatically impaired
subjects.
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Age:
Although a general conclusion about the effects of age on the pharmacokinetics of Selegiline is not
warranted because of the size of the sample evaluated (12 subjects greater than 60 years of age, 12 subjects
between the ages of 18 to 30), systemic exposure was about twice as great in older as compared to a
younger population given a single oral dose of 10 mg.
Gender:
No information is available on the effects of gender on the pharmacokinetics of Selegiline.
INDICATIONS AND USAGE
ELDEPRYL is indicated as an adjunct in the management of Parkinsonian patients being treated with
levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no
evidence from controlled studies that Selegiline has any beneficial effect in the absence of concurrent
levodopa therapy.
Evidence supporting this claim was obtained in randomized controlled clinical investigations that compared
the effects of added Selegiline or placebo in patients receiving levodopa/carbidopa. Selegiline was
significantly superior to placebo on all three principal outcome measures employed: change from baseline
in daily levodopa/carbidopa dose, the amount of `off' time, and patient self–rating of treatment success.
Beneficial effects were also observed on other measures of treatment success (e.g., measures of reduced
end of dose akinesia, decreased tremor and sialorrhea, improved speech and dressing ability and improved
overall disability as assessed by walking and comparison to previous state).
CONTRAINDICATIONS
ELDEPRYL is contraindicated in patients with a known hypersensitivity to this drug.
ELDEPRYL is contraindicated for use with meperidine (DEMEROL & other trade names). This
contraindication is often extended to other opioids. (See Drug Interactions.)
WARNINGS
Selegiline should not be used at daily doses exceeding those recommended (10 mg/day) because of the
risks associated with nonselective inhibition of MAO. (See CLINICAL PHARMACOLOGY.)
The selectivity of Selegiline for MAO B may not be absolute even at the recommended daily dose of 10 mg
a day. Rare cases of hypertensive reactions associated with ingestion of tyramine–containing foods have
been reported in patients taking the recommended daily dose of Selegiline. The selectivity is further
diminished with increasing daily doses. The precise dose at which Selegiline becomes a non-selective
inhibitor of all MAO is unknown, but may be in the range of 30 to 40 mg a day.
Severe CNS toxicity associated with hyperpyrexia and death have been reported with the combination of
tricyclic antidepressants and non–selective MAOIs (NARDIL, PARNATE). A similar reaction has been
reported for a patient on amitriptyline and ELDEPRYL. Another patient receiving protriptyline and
ELDEPRYL developed tremors, agitation, and restlessness followed by unresponsiveness and death two
weeks after ELDEPRYL was added. Related adverse events including hypertension, syncope, asystole,
diaphoresis, seizures, changes in behavioral and mental status, and muscular rigidity have also been
reported in some patients receiving ELDEPRYL and various tricyclic antidepressants.
Serious, sometimes fatal, reactions with signs and symptoms that may include hyperthermia, rigidity,
myoclonus, autonomic instability with rapid fluctuations of the vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma have been reported with patients receiving a
combination of fluoxetine hydrochloride (PROZAC) and non–selective MAOIs. Similar signs have been
reported in some patients on the combination of ELDEPRYL (10 mg a day) and selective serotonin
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reuptake inhibitors including fluoxetine, sertraline and paroxetine.
Since the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid this
combination of ELDEPRYL and tricyclic antidepressants as well as ELDEPRYL and selective serotonin
reuptake inhibitors. At least 14 days should elapse between discontinuation of ELDEPRYL and initiation
of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitors. Because of the long
half-lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine
has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine
and initiation of treatment with ELDEPRYL.
PRECAUTIONS
General:
Some patients given Selegiline may experience an exacerbation of levodopa associated side effects,
presumably due to the increased amounts of dopamine reaction with super sensitive, post–synaptic
receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa by
approximately 10 to 30%.
The decision to prescribe Selegiline should take into consideration that the MAO system of enzymes is
complex and incompletely understood and there is only a limited amount of carefully documented clinical
experience with Selegiline. Consequently, the full spectrum of possible responses to Selegiline may not
have been observed in pre–marketing evaluation of the drug. It is advisable, therefore, to observe patients
closely for atypical responses.
Information for Patients:
Patients should be advised of the possible need to reduce levodopa dosage after the initiation of
ELDEPRYL therapy.
Patients (or their families if the patient is incompetent) should be advised not to exceed the daily
recommended dose of 10 mg. The risk of using higher daily doses of Selegiline should be explained, and a
brief description of the `cheese reaction' provided. Rare hypertensive reactions with Selegiline at
recommended doses associated with dietary influences have been reported.
Consequently, it may be useful to inform patients (or their families) about the signs and symptoms
associated with MAOI induced hypertensive reactions. In particular, patients should be urged to report,
immediately, any severe headache or other atypical or unusual symptoms not previously experienced.
Laboratory Tests:
No specific laboratory tests are deemed essential for the management of patients on ELDEPRYL. Periodic
routine evaluation of all patients, however, is appropriate.
Drug Interactions:
The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in
some patients receiving the combination of Selegiline and meperidine. Symptoms usually resolve over
days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs.
Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients
receiving this combination (see CONTRAINDICATIONS ). Severe toxicity has also been reported in
patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin
reuptake inhibitors and ELDEPRYL. (See WARNINGS for details). One case of hypertensive crisis has
been reported in a patient taking the recommended doses of Selegiline and a sympathomimetic medication
(ephedrine).
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Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Assessment of the carcinogenic potential of Selegiline in mice and rats is ongoing.
Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in
Salmonella typhimurium and in an in vivo chromosomal aberration assay. While these studies provide
some reassurance that Selegiline is not mutagenic or clastogenic, they are not definitive because of
methodological limitations. No definitive in vitro chromosomal aberration or in vitro mammalian gene
mutation assays have been performed.
The effect of Selegiline on fertility has not been adequately assessed.
Pregnancy:
Pregnancy Category C: No teratogenic effects were observed in a study of embryo–fetal development in
Sprague–Dawley rats at oral doses of 4, 12, and 36 mg/kg or 4, 12 and 35 times the human therapeutic dose
on a mg/m 2 basis. No teratogenic effects were observed in a study of embryo–fetal development in New
Zealand White rabbits at oral doses of 5, 25, and 50 mg/kg or 10, 48, and 95 times the human therapeutic
dose on a mg/m 2 basis; however, in this study, the number of litters produced at the two higher doses was
less than recommended for assessing teratogenic potential. In the rat study, there was a decrease in fetal
body weight at the highest dose tested. In the rabbit study, increases in total resorptions and % post–
implantation loss, and a decrease in the number of live fetuses per dam occurred at the highest dose tested.
In a peri – and postnatal development study in Sprague–Dawley rats (oral doses of 4, 16, and 64 mg/kg or
4, 15, and 62 times the human therapeutic dose on a mg/m 2 basis), an increase in the number of stillbirths
and decreases in the number of pups per dam, pup survival, and pup body weight (at birth and throughout
the lactation period) were observed at the two highest doses. At the highest dose tested, no pups born alive
survived to Day 4 postpartum. Postnatal development at the highest dose tested in dams could not be
evaluated because of the lack of surviving pups. The reproductive performance of the untreated off–spring
was not assessed.
There are no adequate and well–controlled studies in pregnant women. Selegiline should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers:
It is not known whether Selegiline hydrochloride is excreted in human milk. Because many drugs are
excreted in human milk, consideration should be given to discontinuing the use of all but absolutely
essential drug treatments in nursing women.
Pediatric Use:
The effects of Selegiline hydrochloride in children have not been evaluated.
ADVERSE REACTIONS
Introduction:
The number of patients who received Selegiline in prospectively monitored pre-marketing studies is
limited. While other sources of information about the use of Selegiline are available (e.g., literature
reports, foreign post–marketing reports, etc.) they do not provide the kind of information necessary to
estimate the incidence of adverse events. Thus, overall incidence figures for adverse reactions associated
with the use of Selegiline cannot be provided. Many of the adverse reactions seen have also been reported
as symptoms of dopamine excess.
Moreover, the importance and severity of various reactions reported often cannot be ascertained. One
index of relative importance, however, is whether or not a reaction caused treatment discontinuation. In
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prospective pre–marketing studies, the following events led, in decreasing order of frequency, to
discontinuation of treatment with Selegiline: nausea, hallucinations, confusion, depression, loss of balance,
insomnia, orthostatic hypotension, increased akinetic involuntary movements, agitation, arrhythmia,
bradykinesia, chorea, delusions, hypertension, new or increased angina pectoris, and syncope. Events
reported only once as a cause of discontinuation are ankle edema, anxiety, burning lips/mouth,
constipation, drowsiness/lethargy, dystonia, excess perspiration, increased freezing, gastrointestinal
bleeding, hair loss, increased tremor, nervousness, weakness, and weight loss.
Experience with ELDEPRYL obtained in parallel, placebo controlled, randomized studies provides only a
limited basis for estimates of adverse reaction rates. The following reactions that occurred with greater
frequency among the 49 patients assigned to Selegiline as compared to the 50 patients assigned to placebo
in the only parallel, placebo controlled trial performed in patients with Parkinson's disease are shown in the
following Table. None of these adverse reactions led to a discontinuation of treatment.
INCIDENCE OF TREATMENTEMERGENT ADVERSE EXPERIENCES IN THE
PLACEBO-CONTROLLED
CLINICAL TRIAL
Adverse Event
Number of Patients Reporting Events
Selegiline hydrochloride
N=49 placebo
N=50
Nausea
10 3
Dizziness/Lightheaded/Fainting
7 1
Abdominal Pain
4 2
Confusion
3 0
Hallucinations
3 1
Dry mouth
3 1
Vivid Dreams
2 0
Dyskinesias
2 5
Headache
2 1
The following events were reported once in either or both groups:
Ache, generalized
1 0
Anxiety/Tension
1 1
Anemia
0 1
Diarrhea
1 0
CSB 1/2/03
Hair Loss
0 1
Insomnia
1 1
Lethargy
1 0
Leg pain
1 0
Low back pain
1 0
Malaise
0 1
Palpitations
1 0
Urinary Retention
1 0
Weight Loss
1 0
In all prospectively monitored clinical investigations, enrolling approximately 920 patients, the following
adverse events, classified by body system, were reported.
Central Nervous System:
Motor/Coordination/Extrapyramidal:
increased tremor, chorea, loss of balance, restlessness, blepharospasm, increased bradykinesia, facial
grimace, falling down, heavy leg, muscle twitch*, myoclonic jerks*, stiff neck, tardive dyskinesia, dystonic
symptoms, dyskinesia, involuntary movements, freezing, festination, increased apraxia, muscle cramps.
Mental Status/Behavioral/Psychiatric:
hallucinations, dizziness, confusion, anxiety, depression, drowsiness, behavior/mood change,
dreams/nightmares, tiredness, delusions, disorientation, lightheadedness, impaired memory*, increased
energy*, transient high*, hollow feeling, lethargy/malaise, apathy, overstimulation, vertigo, personality
change, sleep disturbance, restlessness, weakness, transient irritability.
Pain/Altered Sensation:
headache, back pain, leg pain, tinnitus, migraine, supraorbital pain, throat burning, generalized ache, chills,
numbness of toes/fingers, taste disturbance.
Autonomic Nervous System:
dry mouth, blurred vision, sexual dysfunction.
Cardiovascular:
orthostatic hypotension, hypertension, arrhythmia, palpitations, new or increased angina pectoris,
hypotension, tachycardia, peripheral edema, sinus bradycardia, syncope.
CSB 1/2/03
Gastrointestinal:
nausea/vomiting, constipation, weight loss, anorexia, poor appetite, dysphagia, diarrhea, heartburn, rectal
bleeding, bruxism*, gastrointestinal bleeding (exacerbation of preexisting ulcer disease).
Genitourinary/Gynecologic/Endocrine:
slow urination, transient anorgasmia*, nocturia, prostatic hypertrophy, urinary hesitancy, urinary retention,
decreased penile sensation*, urinary frequency.
Skin and Appendages:
increased sweating, diaphoresis, facial hair, hair loss, hematoma, rash, photosensitivity.
Miscellaneous:
asthma, diplopia, shortness of breath, speech affected.
Postmarketing Reports:
The following experiences were described in spontaneous post–marketing reports. These reports do not
provide sufficient information to establish a clear causal relationship with the use of ELDEPRYL.
CNS:
Seizure in dialyzed chronic renal failure patient on concomitant medications.
*indicates events reported only at doses greater than 10 mg/day.
OVERDOSAGE
Selegiline:
No specific information is available about clinically significant overdoses with ELDEPRYL. However,
experience gained during Selegiline's development reveals that some individuals exposed to doses of 600
mg of d,l–Selegiline suffered severe hypotension and psychomotor agitation.
Since the selective inhibition of MAO B by Selegiline hydrochloride is achieved only at doses in the range
recommended for the treatment of Parkinson's disease (e.g., 10 mg/day), overdoses are likely to cause
significant inhibition of both MAO A and MAO B. Consequently, the signs and symptoms of overdose
may resemble those observed with marketed non-selective MAO inhibitors [e.g., tranylcypromine
(PARNATE), isocarboxazide (MARPLAN), and phenelzine (NARDIL)].
Overdose with Non-Selective MAO Inhibition:
NOTE:
This section is provided for reference; it does not describe events that have actually been observed with
Selegiline in overdose.
Characteristically, signs and symptoms of non–selective MAOI overdose may not appear immediately.
Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly,
the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death
has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient
observation and monitoring for a period of at least two days following the ingestion of such drugs in
CSB 1/2/03
overdose, is strongly recommended.
The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of
drug consumed. The central nervous and cardiovascular systems are prominently involved.
Signs and symptoms of overdosage may include, alone or in combination, any of the following:
drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations,
trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and
vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool,
clammy skin.
Treatment Suggestions For Overdose:
NOTE:
Because there is no recorded experience with Selegiline overdose, the following suggestions are
offered based upon the assumption that Selegiline overdose may be modeled by non-selective MAOI
poisoning. In any case, up-to-date information about the treatment of overdose can often be obtained
from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control
Centers are listed in the Physicians' Desk Reference (PDR).
Treatment of overdose with non-selective MAOIs is symptomatic and supportive. Induction of emesis or
gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has
been protected against aspiration. Signs and symptoms of central nervous system stimulation, including
convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and
central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated
with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute
pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor
response.
Respiration should be supported by appropriate measures, including management of the airway, use of
supplemental oxygen, and mechanical ventilatory assistance, as required.
Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required.
Maintenance of fluid and electrolyte balance is essential.
DOSAGE AND ADMINISTRATION
ELDEPRYL is intended for administration to Parkinsonian patients receiving levodopa/carbidopa therapy
who demonstrate a deteriorating response to this treatment. The recommended regimen for the
administration of ELDEPRYL is 10 mg per day administered as divided doses of 5 mg each taken at
breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration
of higher doses. Moreover, higher doses should ordinarily be avoided because of the increased risk of side
effects.
After two to three days of Selegiline treatment, an attempt may be made to reduce the dose of
levodopa/carbidopa. A reduction of 10 to 30% was achieved with the typical participant in the domestic
placebo controlled trials who was assigned to Selegiline treatment. Further reductions of
levodopa/carbidopa may be possible during continued Selegiline therapy.
HOW SUPPLIED
ELDEPRYL capsules are available containing 5 mg of Selegiline hydrochloride. Each aqua blue capsule is
band imprinted with the Somerset logo on the cap and "Eldepryl 5 mg" on the body.
They are available as:
CSB 1/2/03
NDC 39506-022-60 bottles of 60 capsules.
NDC 39506-022-30 bottles of 300 capsules.
Store at controlled room temperature, 59° to 86°F (15° to 30°C).
Rx only
SOMERSET
PHARMACEUTICALS, INC .
Tampa, FL 33607
Literature issued July 1998
ELD:R16C
PRODUCT PHOTO(S):
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict
actual or relative size.
The product samples shown here have been supplied by the manufacturer and reproduced in full color by
PDR as a quick-reference identification aid. While every effort has been made to assure accurate
reproduction, please remember that any visual identification should be considered preliminary. In cases of
poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.
----------------------------------------------------------------------------------------------------------------------------------------------Copyright 2002 Thomson Medical Economics All Rights Reserved.
-----------------------------------------------------------------------© 1974 - 2002 Thomson MICROMEDEX. All rights reserved. MICROMEDEX(R) Healthcare Series Vol.
113 expires 9/2002
- Content for use only by healthcare professionals in conjunction with clinical data. See complete
Warranties and disclaimers.
CSB 1/2/03
Appendix C
Physicians’ Desk Reference Information on NARDIL
SELEGILINE (ELDEPRYL) MAY ACT AS A NON-SLECTIVE MAO INHIBITOR AT HIGH
DOSES THEREFORE INFORMATION ON NARDIL IS PROVIDED AS IT IS A PROTOTYPE
FOR NON-SELECTIVE MAO INHIBITORS.
INFORMATION ON NON-SELECTIVE MAO INHIBITORS ARE CONTAINED IN THE PDR
LISTING FOR NARDIL ATTACHED BELOW:
PHYSICIANS' DESK REFERENCE
-----------------------------------------------------------------------PDR® entry for
Nardil Tablets (Parke–Davis)
DESCRIPTION
CHEMICAL STRUCTURE
CLINICAL PHARMACOLOGY
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
DRUG INTERACTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
PRODUCT PHOTO(S)
DESCRIPTION
Nardil® (phenelzine sulfate) is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a
hydrazine derivative. It is a molecular weight of 234.27 and is chemically described as C 8 H 12 N 2 ·N 2
SO 4. Its chemical structure is shown below:
Molecular weight: 234.27
Each Nardil tablet for oral administration contains phenelzine sulfate equivalent to 15 mg of phenelzine
base. Inactive ingredients include: acacia NF; calcium carbonate; carnauba wax, NF; corn-starch, NF; FD
and C yellow No. 6; gelatin, NF; kaolin, USP; magnesium stearate, NF; mannitol, USP; pharmaceutical
glaze, NF; povidone, USP; sucrose, NF; talc, USP; white wax, NF; white wheat flour.
CSB 1/2/03
CLINICAL PHARMACOLOGY
Monoamine oxidase is a complex enzyme system, widely distributed throughout the body. Drugs
that inhibit monoamine oxidase in the laboratory are associated with a number of clinical effects.
Thus, it is unknown whether MAO inhibition per se, other pharmacologic actions, or an interaction
of both is responsible for the clinical effects observed. Therefore, the physician should become
familiar with all the effects produced by drugs of this class.
INDICATIONS AND USAGE
Nardil has been found to be effective in depressed patients clinically characterized as "atypical,"
"nonendogenous," or "neurotic." These patients often have mixed anxiety and depression and phobic or
hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed
patients with endogenous features.
Nardil should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients
who have failed to respond to the drugs more commonly used for these conditions.
CONTRAINDICATIONS
Nardil should not be used in patients who are hypersensitive to the drug or its ingredients, with
pheochromocytoma, congestive heart failure, a history of liver disease, or abnormal liver function tests.
The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in
hypertensive crises (see WARNINGS ). Therefore, patients being treated with Nardil should not take
sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine and
norepinephrine) or related compounds (including methyldopa, L–dopa, L–tryptophan, L–tyrosine, and
phenylalanine). Hypertensive crises during Nardil therapy may also be caused by the ingestion of foods
with a high concentration of tyramine or dopamine. Therefore, patients being treated with Nardil should
avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking,
or bacterial contamination. Patients should also avoid cheeses (especially aged varieties), pickled herring,
beer, wine, liver, yeast extract (including brewer's yeast in large quantities), dry sausage (including Genoa
salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (fava beans), and yogurt.
Excessive amounts of caffeine and chocolate may also cause hypertensive reactions.
Nardil should not be used in combination with dextromethorphan or with CNS depressants such as alcohol
and certain narcotics. Excitation, seizures, delirium, hyperpyrexia, circulatory collapse, coma, and death
have been reported in patients receiving MAOI therapy who have been given a single dose of meperidine.
Nardil should not be administered together with or in rapid succession to other MAO inhibitors because
HYPERTENSIVE CRISES and convulsive seizures, fever, marked sweating, excitation, delirium, tremor,
coma, and circulatory collapse may occur.
A List of MAO Inhibitors by generic name follows:
pargyline hydrochloride
pargyline hydrochloride
and methylclothiazide
furazolidone
isocarboxazid
procarbazine
tranylcypromine
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Nardil should also not be used in combination with buspirone HCl, since several cases of elevated blood
pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCl. At
least 10 days should elapse between the discontinuation of Nardil and the institution of another
antidepressant or buspirone HCl, or the discontinuation of another MAO inhibitor and the institution of
Nardil.
There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and
death) when serotoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline,
venlafaxine) have been combined with an MAO inhibitor. Therefore the concomitant use of Nardil with
serotoninergic agents is contraindicated (see PRECAUTIONS -- Drug Interactions ). Allow at least five
weeks between discontinuation of fluoxetine and initiation of Nardil and at least 10 days between
discontinuation of Nardil and initiation of fluoxetine, or other serotoninergic agents. Before initiating
Nardil after using other serotoninergic agents, a sufficient amount of time must be allowed for clearance of
the serotoninergic agent and its active metabolites.
The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic
syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia,
myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs.
The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®) is
contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation
of treatment with bupropion hydrochloride.
Patients taking Nardil should not undergo elective surgery requiring general anesthesia. Also, they should
not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible
combined hypotensive effects of Nardil and spinal anesthesia should be kept in mind. Nardil should be
discontinued at least 10 days prior to elective surgery.
MAO inhibitors, including Nardil, are contraindicated in patients receiving guanethidine.
WARNINGS
The most serious reactions to Nardil involve changes in blood pressure.
Hypertensive Crises: The most important reaction associated with Nardil administration is the occurrence
of hypertensive crises, which have sometimes been fatal.
These crises are characterized by some or all of the following symptoms: occipital headache which may
radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever
and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia
may be present and can be associated with constricting chest pain.
NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure.
Blood pressure should be observed frequently to detect evidence of any pressor response in all patients
receiving Nardil. Therapy should be discontinued immediately upon the occurrence of palpitation or
frequent headaches during therapy.
Recommended treatment in hypertensive crisis: If a hypertensive crisis occurs, Nardil should be
discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the
basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg
intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an
excessive hypotensive effect. Fever should be managed by means of external cooling.
Warning to the Patient: All patients should be warned that the following foods, beverages, and medications
must be avoided while taking Nardil, and for two weeks after discontinuing use.
CSB 1/2/03
Foods and Beverages To Avoid
Meat and Fish
Pickled herring
Liver
Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna)
Vegetables
Broad bean pods (fava bean pods)
Sauerkraut
Dairy Products
Cheese (cottage cheese and cream cheese are allowed)
Yogurt
Beverages
Beer and wine
Alcohol–free and reduced–alcohol beer and wine products
Miscellaneous
Yeast extract (including brewer's yeast in large quantities)
Meat extract
Excessive amounts of chocolate and caffeine
Also, any spoiled or improperly refrigerated, handled, or stored protein–rich foods such as meats, fish, and
dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation,
or smoking to improve flavor should be avoided.
OTC Medications To Avoid
Cold and cough preparations (including those containing dextromethorphan)
Nasal decongestants (tablets, drops, or spray)
Hay–fever medications
Sinus medications
Asthma inhalant medications
Anti–appetite medicines
Weight–reducing preparations
"Pep" pills
CSB 1/2/03
L–tryptophan containing preparations
Also, certain prescription drugs should be avoided. Therefore, patients under the care of another physician
or dentist should inform him/her they are taking Nardil.
Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction
characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception
of dextromethorphan which may cause reactions similar to those seen with meperidine. Also, there has
been a report of an interaction between Nardil and dextromethorphan (ingested as a lozenge) causing
drowsiness and bizarre behavior.
Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.
Concomitant Use with Dibenzazepine Derivative Drugs
If the decision is made to administer Nardil concurrently with other antidepressant drugs, or within less
than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the
physician regarding the possibility of adverse drug interaction.
A List of Dibenzazepine Derivative Drugs by generic name follows:
nortriptyline hydrochloride
amitriptyline hydrochloride
amitriptyline hydrochloride
perphenazine and amitriptyline
hydrochloride
perphenazine and amitriptyline
hydrochloride
clomipramine hydrochloride
desipramine hydrochloride
desipramine hydrochloride
imipramine hydrochloride
doxepin
doxepin
carbamazepine
cyclobenzaprine HCl
amoxapine
maprotiline HCl
trimipremine maleate
protriptyline HCl
CSB 1/2/03
mirtazapine
Nardil should be used with caution in combination with antihypertensive drugs, including thiazide diuretics
and (beta) – blockers, since exaggerated hypotensive effects may result.
Use in Pregnancy: The safe use of Nardil during pregnancy or lactation has not been established. The
potential benefit of this drug, if used during pregnancy, lactation, or in women of childbearing age, should
be weighed against the possible hazard to the mother or fetus.
Doses of Nardil in pregnant mice well exceeding the maximum recommended human dose have caused a
significant decrease in the number of viable offspring per mouse. In addition, the growth of young dogs
and rats has been retarded by doses exceeding the maximum human dose.
Use in Pediatric Patients: Nardil is not recommended for pediatric patients under 16 years of age, since
there are no controlled studies of safety in this age group. Nardil, as with other hydrazine derivatives, has
been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice.
PRECAUTIONS
In depressed patients, the possibility of suicide should always be considered and adequate precautions
taken. It is recommended that careful observations of patients undergoing Nardil treatment be maintained
until control of depression is achieved. If necessary, additional measures (ECT, hospitalization, etc) should
be instituted.
All patients undergoing treatment with Nardil should be closely followed for symptoms of postural
hypotension. Hypotensive side effects have occurred in hypertensive as well as normotensive and
hypotensive patients. Blood pressure usually returns to pretreatment levels rapidly when the drug is
discontinued or the dosage is reduced.
Because the effect of Nardil on the convulsive threshold may be variable, adequate precautions should be
taken when treating epileptic patients.
Of the more severe side effects that have been reported with any consistency, hypomania has been the most
common. This reaction has been largely limited to patients in whom disorders characterized by
hyperkinetic symptoms coexist with, but are obscured by, depressive affect; hypomania usually appeared as
depression improved. If agitation is present, it may be increased with Nardil. Hypomania and agitation
have also been reported at higher than recommended doses or following long–term therapy.
Nardil may cause excessive stimulation in schizophrenic patients; in manic–depressive states it may result
in a swing from a depressive to a manic phase.
MAO inhibitors, including Nardil, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates
should be given at a reduced dose with Nardil.
MAO inhibitors inhibit the destruction of serotonin and norepinephrine, which are believed to be released
from tissue stores by rauwolfia alkaloids. Accordingly, caution should be exercised when rauwolfia is used
concomitantly with an MAO inhibitor, including Nardil.
There is conflicting evidence as to whether or not MAO inhibitors affect glucose metabolism or potentiate
hypoglycemic agents. This should be kept in mind if Nardil is administered to diabetics.
Drug Interactions
In patients receiving nonselective monoamine oxidase inhibitors (MAOIs)in combination with
serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafexine)
there have been reports of serious, sometimes fatal, reactions. Because Nardil is a MAOI, Nardil should
not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS ).
CSB 1/2/03
Geriatric Use
Clinical studies of Nardil did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection for
an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
Nardil is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout
the body, diverse pharmacologic effects can be expected to occur. When they occur, such effects tend to be
mild or moderate in severity (see below), often subside as treatment continues, and can be minimized by
adjusting dosage; rarely is it necessary to institute counteracting measures or to discontinue Nardil.
Common side effects include:
Nervous System --Dizziness, headache, drowsiness, sleep disturbances (including insomnia and
hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia.
Gastrointestinal --Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases
(without accompanying signs and symptoms).
Metabolic --Weight gain.
Cardiovascular --Postural hypotension, edema.
Genitourinary --Sexual disturbances, eg, anorgasmia and ejaculatory disturbances and impotence.
Less common mild to moderate side effects (some of which have been reported in a single patient or by a
single physician) include:
Nervous System --Jitteriness, palilalia, euphoria, nystagmus, paresthesias.
Genitourinary --Urinary retention.
Metabolic-- Hypernatremia.
Dermatologic --Pruritus, Skin rash, sweating.
Special Senses --Blurred vision, glaucoma.
Although reported less frequently, and sometimes only once, additional severe side effects include:
Nervous System --Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety
reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT.
Gastrointestinal --To date, fatal progressive necrotizing hepatocellular damage has been reported in a very
few patients. Reversible jaundice.
Hematologic --Leukopenia.
Immunologic --Lupus-like syndrome.
Metabolic --Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia,
CSB 1/2/03
tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may
resemble an overdose).
Respiratory --Edema of the glottis.
General --Fever associated with increased muscle tone.
Withdrawal may be associated with nausea, vomiting, and malaise.
An uncommon withdrawal syndrome following abrupt withdrawal of Nardil has been infrequently reported.
Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and
may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome
generally responds to reinstitution of low–dose Nardil therapy followed by cautious downward titration and
discontinuation.
DOSAGE AND ADMINISTRATION
Initial dose: The usual starting dose of Nardil is one tablet (15 mg) three times a day.
Early phase treatment: Dosage should be increased to at least 60 mg per day at a fairly rapid pace
consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg per day to obtain
sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg has
been continued for at least 4 weeks.
Maintenance dose: After maximum benefit from Nardil is achieved, dosage should be reduced slowly
over several weeks. Maintenance dose may be as low as one tablet, 15 mg, a day or every other day, and
should be continued for as long as is required.
OVERDOSAGE
Note --For management of hypertensive crises see WARNINGS section.
Accidental or intentional overdosage may be more common in patients who are depressed. It should be
remembered that multiple drugs and/or alcohol may have been ingested.
Depending on the amount of overdosage with Nardil, a varying and mixed clinical picture may develop,
including signs and symptoms of central nervous system and cardiovascular stimulation and/or depression.
Signs and symptoms may be absent or minimal during the initial 12–hour period following ingestion and
may develop slowly thereafter, reaching a maximum in 24–48 hours. Death has been reported following
overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring
throughout this period, is essential.
Signs and symptoms of overdosage may include, alone or in combination, any of the following:
drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations,
trismus, opisthotonus, rigidity, convulsions, and coma; rapid and irregular pulse, hypertension,
hypotension, and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia,
diaphoresis, and cool, clammy skin.
Treatment: Intensive symptomatic and supportive treatment may be required. Induction of emesis or
gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has
been protected against aspiration. Signs and symptoms of central nervous system stimulation, including
convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and
central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated
with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of dilute
pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor
CSB 1/2/03
response.
Respiration should be supported by appropriate measures, including management of the airway, use of
supplemental oxygen, and mechanical ventilatory assistance, as required.
Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required.
Maintenance of fluid and electrolyte balance is essential.
There are no data on the lethal dose in man. The pathophysiologic effects of massive overdosage may
persist for several days, since the drug acts by inhibiting physiologic enzyme systems. With symptomatic
and supportive measures, recovery from mild overdosage may be expected within 3 to 4 days.
Hemodialysis, peritoneal dialysis, and charcoal hemoperfusion may be of value in massive overdosage, but
sufficient data are not available to recommend their routine use in these cases.
Toxic blood levels of phenelzine have not been established, and assay methods are not practical for clinical
or toxicological use.
HOW SUPPLIED
Each Nardil tablet is orange, biconvex, glossy sugar–coated, and imprinted with "P–D 270" in brown ink
and contains phenelzine sulfate equivalent to 15 mg of phenelzine base.
N 0071–0270–24 Bottles of 100
Storage: Store between 15°–30° C (59°–86°F).
Rx only
US Patent 3,314,855
Revised August 1998
0270G081
PRODUCT PHOTO(S):
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict
actual or relative size.
The product samples shown here have been supplied by the manufacturer and reproduced in full color by
PDR as a quick-reference identification aid. While every effort has been made to assure accurate
reproduction, please remember that any visual identification should be considered preliminary. In cases of
poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.
----------------------------------------------------------------------------------------------------------------------------------------------Copyright 2002 Thomson Medical Economics All Rights Reserved.
-----------------------------------------------------------------------© 1974 –2002 Thomson MICROMEDEX. All rights reserved. MICROMEDEX(R) Healthcare Series Vol.
113 expires 9/2002
- Content for use only by healthcare professionals in conjunction with clinical data. See complete
Warranties and disclaimers.
CSB 1/2/03